Conjugates of catecholamines. III. Synthesis and characterization of monodisperse oligopeptides conjugates related to isoproterenol

Jacobson, Ken; Verlander, Michael S.; Rosenkranz, Roberto P.; Melmon, Kenneth L.; Goodman, Murray

doi:10.1111/j.1399-3011.1983.tb02095.x

Cited by 8 publications

(2 citation statements)

References 22 publications

(13 reference statements)

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“…Although these studies were highly diverse, both from the standpoint of the chemistry of attachment of the drug t o the carrier and also the nature of the different carriers themselves. they have provided important evidence for the potential of dramatically altering the properties of these drugs through systematic variation of the are amino (9. lo), carboxyl (6,9,11,12), and hydroxyl (l,9).…”

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“…Previously, we have reported on the syntheses and biological activities of peptide conjugates ranging in size from those derived from a single, blocked p-aminophenylalanine residue to those derived from isomeric pentapeptides (6, 9,12,[15][16][17]. The peptide conjugates which have been tested in vivo, although of modest potency, have shown significant increases in duration of action compared to (+)-isoproterenol (15,16).…”

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Conjugates of catecholamines. VII. Synthesis and β‐adrenergic activity of peptide catecholamine conjugates†

Fukuda

Beechan

Verlander

et al. 1987

International Journal of Peptide and Protein Research

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A series of novel catecholamine derivatives has been prepared in which one of the N‐methyl substituents of isoproterenol has been extended by a spacer consisting of a chain of four methylenes which terminates with an amide linkage to a peptide, the point of attachment being via the aromatic amino group of p‐aminophenylalanine. In one of the derivatives, two catecholamines are attached to the same peptide in this manner. The peptides, which range in size from three to eight amino acid residues and contain phenylalanine, glycine, and L‐α‐amino‐δ‐hydroxyvaleric acid, were synthesized via stepwise and fragment condensation techniques. The β‐adrenergic agonist activities of the derivatives were evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells.

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Conjugates of catecholamines. VII. Synthesis and β‐adrenergic activity of peptide catecholamine conjugates†

Fukuda

Beechan

Verlander

et al. 1987

International Journal of Peptide and Protein Research

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Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

2002

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Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful. This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.

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Optically Pure Isoproterenol Analogues With Side Chains Containing an Amide Bond: Synthesis and biological properties

Märki

Crameri

Eigenmann

et al. 1988

Helvetica Chimica Acta

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The isoproterenol analogues 4a and 4b, synthesized as mixtures of diastereoisomers, were shown to possess very potent 8-adrenoceptor agonistic activity. Therefore, the four possible diastereoisomers of 4a have been synthesized and tested for inotropic activity. The (6R,2'R)-diastereoisomer turned out to be the most interesting one. Consequently, also (6R,2'R)-4b has been prepared and tested. For the diastereoselective synthesis, three variants have been elaborated: i ) coupling of epoxides 12 with amines 27 (Scheme 6) ; iz) coupling of the activated glycol 17 with the amine 22 (Scheme 8) ; iii) diastereoselective hydrogenation of the amino ketone 31 (Scheme 7). Both (6R,2'R)-4a and (6R,2'R)-4h show long lasting positive inotropic activity after intravenous as well as oral administration and are at least three times as potent as rue-isoproterenol. In the anesthetized dog, a good separation of positive inotropic and positive chronotropic effects is observed. In conscious dogs, however, heart rate and contractile force increase to the same extent (possibly due to reflex tachycardia).1. Introduction. -Within the scope of studies [ 1-91, the final objective of which is to improve the therapeutic index of drugs by covalent conjugation to carrier molecules, particularly to peptides, Goodman and Melmon and their coworkers investigated numerous compounds which have the skeleton of isoproterenol(2) and can be described by the general formula 3 (Scheme I ) [ 14][7-91. These compounds were synthesized starting from ruc -norepinephrine (1) by reductive amination and, therefore, obtained as mixtures of diastereoisomers. Separation into pure components could not be achieved [l]. In comparison with 2 in four in-vitro test systems, the preparations 4a and 4b attracted particular attention as very potent b-adrenoceptor agonists First, the four diastereoisomers of 4a were synthesized and biologically evaluated. Since (6R,2'R)-4a turned out to be by far the most interesting compound; subsequently, of the more complex structure 4b, only the (6R,2'R)-isomer was prepared and biologically studied.In the following, we report on our synthetic work (Chupt. 2) and on the pharmacological investigation of the optically pure stereoisomers mentioned in comparison to the corresponding mixtures of racemic diastereoisomers (Chupt. 3 ) .

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Conjugates of catecholamines. III. Synthesis and characterization of monodisperse oligopeptides conjugates related to isoproterenol

Cited by 8 publications

References 22 publications

Conjugates of catecholamines. VII. Synthesis and β‐adrenergic activity of peptide catecholamine conjugates†

Conjugates of catecholamines. VII. Synthesis and β‐adrenergic activity of peptide catecholamine conjugates†

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

Optically Pure Isoproterenol Analogues With Side Chains Containing an Amide Bond: Synthesis and biological properties

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